Sorting nexins are a family of mammalian proteins that contain PX domains with close homology to several proteins that are required for normal protein trafficking in yeast. SNX1 and SNX2 are close homologs of Vps5p, a protein involved in retrograde traffic of proteins from late endosomes to the Golgi. SNX3 is the ortholog of Grd19p, a protein required to retain proteins such as Kex2p in the Golgi. SNX8 is a close homolog of Mvp1p, a protein that interacts with a dynamin-like protein (Vps1p). We have obtained cDNAs for several sorting nexins (SNX1-4, 8, and 15), and also obtained cDNAs for human homologs of several other components of the multimeric complex containing Vps5p (i.e., Vps26p, Vps29p, and Vps35p). We have demonstrated that several of these proteins interact with various receptor tyrosine kinases (e.g., receptors for insulin, EGF, and PDGF) and also with the long isoform of the leptin receptor. In addition, we have used the yeast two hybrid system to characterize the interactions among these proteins. The data are consistent with a model in which human Vps35 serves as the core of a multimeric complex by providing binding sites for SNX1, hVps26, and hVps29. Studies are underway to elucidate the roles of these proteins in protein trafficking within mammalian cells. - protein trafficking, vacuolar protein sorting, endosome, lysosome, golgi, insulin, leptin, receptor tyrosine kinase